Structural Genomix, which reported last week that it had taken only a month to convert cDNA for the SARS coronavirus protease into a protein crystal, told ProteoMonitor that it plans to convert the crystal’s binding properties into a drug lead within a six-month time frame.
SGX is not the first company to characterize some aspect of the SARS proteome, or to seek targets for drug discovery. In April, researchers at the University of Manitoba Proteomics Center completed draft sequences of a nucleocapsid protein and a spike glycoprotein made by the SARS coronavirus, and suggested that the nucleocapsid protein might be useful for early diagnostics (see PM 4-21-03, 6-6-03). In addition, the main protease from a coronavirus similar to SARS was recently modeled computationally to look for binding sites.
The next stage of drug discovery for SGX will involve soaking the company’s protease crystals with a mixture of fragments from its internal library, according to Herbert Mutter, SGX’s vice president of finance. The co-crystals will be sent through a particle accelerator called the Advanced Photon Source at the Argonne National Laboratory near Chicago, to see which fragments are binding in the protease’s active sites and how they bind. The fragments that bind will then be tweaked to determine whether they can be made to bind with greater affinity.
SGX, a high-throughput protein crystallization company based in San Diego, says it regularly makes the journey from protein structure to lead in about two to five months using its co-crystallization platform.
The company joined the rush for a SARS drug when its collaborator, the Genome Institute of Singapore, delivered cDNA clones for the SARS coronavirus genome to the company a month ago. Inspired by the precedent of drugs that successfully inhibit the HIV protease, and working from “extensive bioinformatics work,” SGX chose the main protease as its focus. “There are a lot of parallelisms with the HIV protease,” Mutter said. “[Like with HIV], by inhibiting the SARS protease, one could stop the virus from replicating.”
SGX is now shopping for collaboration opportunities related to SARS drug discovery, and its potential partners “run the gamut from biotech companies that specialize in anti-viral programs to big pharma,” Mutter said.
In a collaboration, SGX would provide the crystals and the co-crystallization platform, while the partner might provide initial fragments for protein binding, as well as cell-based assays and animal models that would be used later in the drug discovery process. “They may provide some of the biology and also the downstream development, whereas we would be doing more of the chemistry and obviously the structural biology work,” Mutter said. He added that the six-month time frame he had cited for lead discovery was based on the assumption that SGX would work alone with grant funding, and that if collaborations were formed, they “may not be consistent with this time frame.”
According to Mutter, the significance of SGX’s crystallization feat is that sequences and computer models do not offer the same depth of information for drug discovery that crystallization does. “The thing that is difficult for [models] to predict is the fact that there are conformational changes within the protein as well as the compounds. They are not static — the protein shape doesn’t remain exactly the same when something binds into it,” Mutter said. “So, without having the ability to see it with the crystal structures, [models] are, in fact, best estimates.”
Mutter said that in the case of the protease homology model, the magnitude of error for looking at size relations in structure, in comparison to the numbers found by crystallization, was 2.5 angstroms — a “significant number.” Mutter said that models that go from sequence to structure hit similar roadblocks. “Just because you have sequence that is similar, it doesn’t mean that the structure and shape is going to be the same,” Mutter said.
Ultimately, it’s the importance of the disease itself that drove SGX to add its two cents to the SARS knowledge pool. SGX management “realized SARS was at the forefront of concern as far as world health goes,” Mutter said.
— KAM